Identification of Deleterious NOTCH Mutation as Novel Predictor to Efficacious Immunotherapy in NSCLC
Open Access
- 15 July 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (14), 3649-3661
- https://doi.org/10.1158/1078-0432.ccr-19-3976
Abstract
NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non–small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy. Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del-NOTCHmut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis. Our 3DMed cohort (n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALKWT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46–0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32–0.96; P = 0.035). Del-NOTCHmut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-NOTCHmut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del-NOTCHmut. This work distinguishes del-NOTCHmut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.Keywords
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Funding Information
- National Key Research and Development Program of China (2016YFC1303800)
- National Natural Science Foundation of China (81773056)
This publication has 44 references indexed in Scilit:
- Non-Canonical Notch Signaling in Cancer and ImmunityFrontiers in Oncology, 2014
- Notch1 Is Required for Kras-Induced Lung Adenocarcinoma and Controls Tumor Cell Survival via p53Cancer Research, 2013
- Notch-1 contributes to epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance in non-small cell lung cancer in vitro and in vivoEuropean Journal of Cancer, 2013
- High NOTCH activity induces radiation resistance in non small cell lung cancerRadiotherapy and Oncology, 2013
- A Rare Population of CD24+ITGB4+Notchhi Cells Drives Tumor Propagation in NSCLC and Requires Notch3 for Self-RenewalCancer Cell, 2013
- Regulation of innate and adaptive immunity by NotchNature Reviews Immunology, 2013
- Activation of notch‐1 enhances epithelial–mesenchymal transition in gefitinib‐acquired resistant lung cancer cellsJournal of Cellular Biochemistry, 2011
- Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinomaProceedings of the National Academy of Sciences of the United States of America, 2011
- A method and server for predicting damaging missense mutationsNature Methods, 2010
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005